APOE C130R - GET-Evidence

APOE C130R

(APOE Cys130Arg)

Short summary

This is generally known as the ApoE4 allele of ApoE and is associated with increased risk of Alzheimer’s. 20-25% of individuals are heterozygous for this variant, and 1-2% are homozygous. Data from Khachaturian et al. suggests an average 7% of all individuals developed Alzheimer’s by the age of 80; when this is split by ApoE4 status: 10% of ApoE4 heterozygotes (3% increased attributable risk), 40% of ApoE4 homozygotes (33% increased attributable risk), and 5% of non-carriers (2% decreased attributable risk). Notably, their model suggests 70-75% of people would eventually develop Alzheimer’s by the age of 100 regardless of ApoE4 genotype (and 25-30% are resistant, regardless of genotype), but that ApoE4 variants shift the disease onset to occur significantly earlier (4 years earlier for heterozygous carriers, 13 years for homozygotes).

Variant evidence

Computational

Other variants in this gene are associated with Alzheimer’s, but Polyphen 2 & SIFT predict nonpathogenic

This paper is the one typically cited regarding the effects of ApoE E2 and E4 on the risk of Alzheimer’s disease. Because translating odds ratios to attributable risks is complicated (requiring assumptions regarding allele frequencies and disease frequencies) and because Khachaturian et al. was able to follow a particularly long-lived population, data from Khachaturian et al. is what is used by GET-Evidence for estimating the effect of ApoE4 on Alzheimer’s risk.

The population analyzed in this study notably contains some very old individuals, allowing the authors to carefully study the lifetime influence of ApoE4 on Alzheimer’s disease. They find that, in general, Alzheimer’s disease is best described by a model where a fraction of the population is resistant to the disease and will never develop it no longer how long they live. In this model, 25-30% of individuals appear to be in this “resistant” group.

When individuals are segregated according to ApoE4 carrier status (homozygous, heterozygous, and non-carrier), they find that the age of onset is shifted earlier for carriers of ApoE4 (Figure 3). For non-carriers, ~50% are diagnosed with Alzheimer’s disease by the age of ~95 years. This shifts to ~91 years of age for individuals heterozygous for ApoE4 (~4 years earlier onset) and ~82 years for ApoE4 homozygotes (~13 years earlier onset).

Investigating the incidence of Alzheimer’s by age 80 in their model, 7% of all individuals on average have developed it by this age (Figure 2). Non-carriers have an average rate of ~5%, heterozygotes a rate of ~10% (2x), and homozygotes a rate of ~40% (8x) (from Figure 3). Penetrance in GET-Evidence is evaluated according to these numbers, with 3% increased attributable risk for heterozygotes (from 7%) and 33% increased attributable risk for homozygotes.